title: Co-targeting the EGFR and IGF-IR with anti-EGFR monoclonal antibody ICR62 and the IGF-IR tyrosine kinase inhibitor NVP-AEW541 in colorectal cancer cells.
abstract: The aberrant expression of the epidermal growth factor receptor (EGFR) has been reported in a wide range of epithelial tumours. In some studies, co-expression of insulin-like growth factor receptor-I (IGF-IR) have been associated with resistance to the EGFR inhibitors. Here, we investigated the sensitivity of a panel of human colorectal tumour cell lines, including two newly established lines Colo2 and Colo13, to treatment with anti-EGFR mAb ICR62 and IGF-IR tyrosine kinase inhibitor NVP-AEW541 alone and in combination. We also determined the association between the expression levels of EGFR and IGF-IR with their responses to ICR62 and/or NVP-AEW541. In contrast to DiFi cells, which contained high levels of EGFR but lower level of IGF-IR, the remaining 11 colorectal tumour cells expressed low levels of both EGFR and IGF-IR and such cells were relatively resistant to ICR62 or NVP-AEW-541 when used alone. Interestingly, compared to the results with the single agent, the effect of combination of NVP-AEW541 and ICR62 was found to be additive on inhibiting the growth of Colo13, CCL235, CCL244 cells but antagonistic in other (CCL218) cells. While overexpression of the EGFR seems to be associated with response to ICR62, no clear correlation was found between the expression levels of EGFR and IGF-IR, or the levels of phosphorylated EGFR and response to treatment with NVP-AEW541, in single or combination setting with ICR62. Our results suggest that combining EGFR and IGF-IR inhibitors may enhance antitumour response in a fraction of colorectal cancer cells and warrants further study in colorectal cancer.
authors.affiliation: Division of Oncology, Postgraduate Medical School, Guildford, UK.
authors.forename: Matthew P
authors.initials: MP
authors.lastname: Cunningham
authors.forename: Hilary
authors.initials: H
authors.lastname: Thomas
authors.forename: Christopher
authors.initials: C
authors.lastname: Marks
authors.forename: Margaret
authors.initials: M
authors.lastname: Green
authors.forename: Zhen
authors.initials: Z
authors.lastname: Fan
authors.forename: Helmout
authors.initials: H
authors.lastname: Modjtahedi
mesh_terms: D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000201:enzymology* / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D004815:Epidermal Growth Factor / Q000378:metabolism; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D045325:HCT116 Cells; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D007335:Insulin-Like Growth Factor II / Q000378:metabolism; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011743:Pyrimidines / Q000008:administration & dosage; D011758:Pyrroles / Q000008:administration & dosage; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000911:Antibodies, Monoclonal; D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D007334:Insulin-Like Growth Factor I; D007335:Insulin-Like Growth Factor II; D020930:MAP Kinase Kinase Kinases; D020928:Mitogen-Activated Protein Kinases; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D011743:Pyrimidines; D011758:Pyrroles; D017526:Receptor, IGF Type 1; C501177:NVP-AEW541; C512478:EGFR protein, human